WO2015070354A1 - Dimères de l'acide acétylsalicylique, leur synthèse, et leurs utilisations pour prévenir et traiter des troubles médiés par le complément - Google Patents

Dimères de l'acide acétylsalicylique, leur synthèse, et leurs utilisations pour prévenir et traiter des troubles médiés par le complément Download PDF

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WO2015070354A1
WO2015070354A1 PCT/CA2014/051097 CA2014051097W WO2015070354A1 WO 2015070354 A1 WO2015070354 A1 WO 2015070354A1 CA 2014051097 W CA2014051097 W CA 2014051097W WO 2015070354 A1 WO2015070354 A1 WO 2015070354A1
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compound according
preventing
effective amount
treating
das
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PCT/CA2014/051097
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Patrick L. Mcgeer
Moonhee Lee
Edith G. Mcgeer
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Aurin Biotech Inc.
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Priority to EP14862004.0A priority Critical patent/EP3071543B1/fr
Priority to ES14862004T priority patent/ES2774776T3/es
Priority to CA2930459A priority patent/CA2930459A1/fr
Priority to JP2016553687A priority patent/JP6464180B2/ja
Priority to US15/036,212 priority patent/US9751824B2/en
Publication of WO2015070354A1 publication Critical patent/WO2015070354A1/fr

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Definitions

  • the present invention pertains to dimers of acetyl salicylic acid, synthesis of such dimers, and use of such dimers to prevent and treat complement-mediated disorders.
  • Mammals are equipped with a powerful innate immune system to ward off challenges from the external environment.
  • Complement is a vital component of that immune protection.
  • complement is a two-edged sword because aberrant complement activation can also damage host tissue.
  • complement activation which exceeds the limitations of the host's protective systems can result in self-damage to viable host tissue.
  • One aspect of the invention provides a compound, namely a dimer of acetyl salicylic acid, or a salt thereof.
  • the dimer may be selected from the group consisting of 4,4'-diacetoxy-[l,l'-biphenyl]-3,3'-dicarboxylic acid (DAS-1) and its isomers, namely 2,4'-diacetoxy-[l,l'-biphenyl]-3,3'-dicarboxylic acid,
  • the dimer may be 4,4'-diacetoxy-[l,l'-biphenyl]-3,3'-dicarboxylic acid (DAS-1), or a salt thereof.
  • the dimer may be selected from the group consisting of 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS-2), and its isomers, namely 2-acetoxy-3-(4-acetoxy-3-carboxybenzyl)benzoic acid,
  • the dimer may 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS-2), or a salt thereof.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers and a pharmaceutically acceptable carrier.
  • the composition is essentially free of monomers and non-dimer multimers of acetyl salicylic acid.
  • Another aspect of the invention provides a method of blocking the C3 convertase stage of the alternative complement pathway, the method comprising administering an effective amount of a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers.
  • a dimer of acetyl salicylic acid such as DAS-1 and DAS-2 or their isomers.
  • Another aspect of the invention provides a method of preventing formation of the membrane attack complex of complement, the method comprising administering an effective amount of a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers.
  • a dimer of acetyl salicylic acid such as DAS-1 and DAS-2 or their isomers.
  • Another aspect of the invention provides a method of preventing or treating a complement-mediated disorder in a mammal, the method comprising administering to the mammal an effective amount of a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers.
  • Another aspect of the invention provides a method of preventing or treating a complement-mediated disorder in a mammal, wherein the disorder is a chronic inflammatory disease, the method comprising administering to the mammal an effective amount of a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers.
  • the disorders include chronic inflammatory and/or degenerative conditions such as, paroxysmal nocturnal hemoglobinemia, age related macular degeneration, Alzheimer's disease, rheumatoid arthritis, atherosclerosis, atypical hemolytic uremia syndrome, multiple sclerosis, malaria infection, Pick's disease, Parkinson's disease, and neuromyelitis optica.
  • the administration step includes oral administration.
  • the methods exclude
  • Another aspect of the invention provides a method of preventing or treating a complement-mediated disorder in a mammal, wherein the disorder is an inflammatory skin disease, the method comprising administering to the mammal an effective amount of a dimer of acetyl salicylic acid, such as DAS-1 and DAS-2 or their isomers.
  • the diseases include androgenetic alopecia, thermal or ultraviolet burn, acne, atopic dermatitis, dandruff/seborrheic dermatitis, pemphigus, erythematosis, cicatricial alopecia and alopecia areata.
  • the administration step includes topical administration.
  • the methods exclude administration of monomers and non-dimer multimers of acetyl salicylic acid.
  • Figure 1 is a schematic diagram showing the sequence of reactions in the classical and alternative complement pathways. The steps blocked by dimers of acetyl salicylic acid, DAS-1 and DAS-2, are shown. For both pathways, the step of insertion of C9 into C5b678 is blocked. For the alternative pathway the step of cleavage of PC3bB by Factor D is blocked.
  • Figures 2A and 2B show mass spectrographic analysis of DAS-1 and DAS-2, respectively, along with their structures and formal names. Mass spectroscopy was run in the +1 mode so that the apparent masses of DAS-1 at 359 and DAS-2 at 373 are +1 greater than their true mass of 358 and 372 respectively.
  • Figure 2C shows structures of isomers of DAS-1 which includes the para-meta, para-ortho, meta-meta, meta-ortho, and ortho-ortho forms along with their proper chemical names.
  • Figure 2D shows structures of the isomers of DAS-2 which includes the para-meta, para-ortho, meta-meta, meta-ortho, and ortho-ortho forms along with their proper chemical names.
  • Figures 3A to 3C are graphs showing CH50 analyses of human red cell hemolysis by zymogen-activated serum from human, rat, cat, and dog. The degree of protection of such hemolysis by DAS-1 ( Figure 3 A), and DAS-2 ( Figure 3B) is shown along with their IC50s. The precursor acetyl salicylic acid (Figure 3C) confers no protection even at 10,000 times higher concentrations.
  • Figures 4A and 4B show Western blot analyses of human red blood cell membranes following exposure to zymogen-activated human serum. Only the classical pathway is activated since the alternative pathway is blocked by antibodies to properdin and Factor D.
  • Figure 4A shows that DAS-1 and DAS-2 do not block the opsonizing steps.
  • Figure 4B shows that DAS-1 and DAS-2 block at the stage where C9 binds to C5b678.
  • Figure 5 shows Western blot analyses of human red blood cell membranes following exposure to zymogen-activated human serum where the classical pathway is blocked by CI inhibitor.
  • Figure 5 shows that DAS-1 and DAS-2 block occurs at the stage where membrane-bound PC3bB is cleaved by Factor D.
  • Factor D does not bind to the complex but remains in solution.
  • Figures 6A and 6B are graphs showing specific binding of DAS- 1 and DAS-2 to C9 and Factor D, but not to C2, C3, C4, C5, C6, C7, C8, Properdin, and Factor B.
  • chronic inflammatory disease refers to diseases or conditions characterized by persistent inflammation, typically in the absence of an identifiable irritant or microbial pathogen.
  • complement-mediated disorder refers to a disorder in which its pathogenesis involves complement activation which exceeds a subject's self-protective mechanisms (such as self-protective proteins including CD 55 (decay accelerating factor), CD 59 (protectin), Factor H, and the like) and causes self-damage to the subject's tissue.
  • self-protective mechanisms such as self-protective proteins including CD 55 (decay accelerating factor), CD 59 (protectin), Factor H, and the like
  • an "effective amount” as used herein refers to the amount of the active agent sufficient to elicit a desired biological response (or, equivalently, to inhibit an undesired biological response).
  • the absolute amount of a particular agent that is effective may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the target tissue, etc.
  • an "effective amount” may be administered in a single dose, or may be achieved by administration of multiple doses.
  • mamammal refers to any mammalian species including without limitation mice, rats, rabbits, dogs, primates and, in particular, humans.
  • prevent and “preventing” as used herein refers to arrest, delay of onset (i.e., the period prior to clinical manifestation of a disease or condition) and/or reduction of the risk of developing or worsening a disease or condition in a subject.
  • subject refers to an individual to whom an agent is to be delivered, e.g., for prophylactic or therapeutic purposes.
  • Preferred subjects are mammals, including humans and domesticated mammals.
  • treat refers to relief, reduction or alleviation of at least one symptom of a disease or condition in a subject.
  • treatment can be diminishment of one or several symptoms of a disease or condition or complete eradication of a disease or condition.
  • One aspect of the invention provides a compound which is a dimer of acetyl salicylic acid.
  • the compound is 2,2'diacetoxy-4,4'biphenyl carboxylic acid, herein described as diacetyl salicylic acid-1 (DAS-1).
  • DAS-1 has a structure which is shown in Fig. 2A.
  • DAS-1 is the para-para form.
  • Other embodiments include isomers of DAS-1 in the para-meta, para-ortho, meta-meta, meta-ortho, and ortho-ortho forms as shown in Fig. 2C.
  • the compound is 4,4'-methylenebis-(2-acetoxybenzoic acid), herein described as diacetyl salicylic acid-2 (DAS-2).
  • DAS-2 has a structure which is shown in Fig. 2B. DAS-2 is the para-para form.
  • Other embodiments include isomers of DAS-2 in para-meta, para-ortho, meta-meta, meta-ortho, and ortho-ortho forms as shown in Fig. 2D.
  • DAS-1 diacetylsalicylic acid-1
  • DAS-2 diacetylsalicylic acid-2
  • the following procedure is an example embodiment for DAS-2.
  • 3-chloro-2-hydroxybenzoic acid is dissolved in lmmol per mL of methanol.
  • a 25% volume of water is added, and the solution cooled to 0°C.
  • a volume of concentrated sulfuric acid equal to 3 times the volume of methanol is added dropwise.
  • a volume of 37% w/v aqueous solution of formaldehyde equal to 40% of the volume of methanol is added dropwise.
  • a further embodiment suitable for synthesis and separation of DAS- 1 and DAS-2 is as follows.
  • the complement system [0033] As shown in Figure 1, the complement system consists of two main pathways: the classical and the alternative. The pathways have differing opsonizing mechanisms, but they have in common assembly of the terminal components to form the membrane attack complex (C5b-9). There are numerous ways by which the pathways may become activated. Zymosan, a glucan found on the surface of fungi, is used as a standard activator for many types of experimental assays. It induces activation of the classical pathway where a target can be presented that needs to be phagocytosed. The Clq component of the CI complex recognizes zymosan.
  • Both pathways result in C5 being cleaved into C5a and C5b.
  • the released C5b fragment can then insert itself into the membranes of nearby cells.
  • C6, C7, C8 and C9 (n) can then become sequentially attached to the membranes.
  • the addition of C9 renders the complex functional by opening holes in the membranes, thus leading to death of the cells. Its physiological purpose is to kill foreign pathogens, but over-activation can result in destruction of host cells by a phenomenon known as bystander lysis.
  • the complement system therefore operates in two parts.
  • the first part is opsonization, which prepares targeted tissue for phagocytosis.
  • the second part is assembly of the membrane attack complex, which has the purpose of killing cells.
  • the former is essential, but the latter is not.
  • approximately 0.12% of Japanese are homozygous for the nonsense CGA-TGA (arginine 95 stop) mutation in exon 4 of C9.
  • These individuals cannot make a functioning membrane attack complex.
  • the same mutation is found in about 0.16% of Koreans, indicating that there are about 40,000 people in the Republic of Korea also leading healthy lives.
  • the inventors have therefore determined from the Japanese and Korean experience that selective inhibition of membrane attack complex formation on a long term basis is a viable therapeutic strategy.
  • the membrane attack complex exacerbates the pathology in all diseases where aberrant complement activation occurs.
  • chronic inflammatory and/or degenerative diseases include, but are not limited to, rheumatoid arthritis, paroxysmal nocturnal hemoglobinemia, atypical hemolytic uremia syndrome, multiple sclerosis, neuromyelitis optica, malaria infection, Alzheimer disease, age related macular degeneration, Parkinson's disease, Pick's disease, amyotrophic lateral sclerosis and atherosclerosis.
  • inflammatory skin diseases include, but are not limited to, androgenetic alopecia (baldness), acne, thermal or ultraviolet burns, atopic dermatitis, seborrheic dermatitis/dandruff, primary cicatricial alopecia, pemphigus, psoriasis, discoid lupus erythematosis, and dermatitus herpetiformis.
  • DAS-1 and DAS-2 as selective inhibitors of the membrane attack complex and C3 convertase
  • C3 convertase complement activation which exceeds the limitations of the host's protective systems can result in self-damage to viable host tissue.
  • Dimers of acetylsalicylic acid, such as DAS-1 and DAS-2 do so by blocking unwanted C3 convertase activity of the alternative pathway, as well as unwanted MAC assembly at the final stage of C9 addition to C5b678 of both the alternative and classical pathways, as shown in Figure 1.
  • FIG. 2 A shows the structure of DAS-1 (C 18 , H 14 , Og) and the match between that structure and the molecular weight of the synthesized product as determined by mass spectro graphic analysis. The analysis was run in the +1 mode giving a value +1 (359) above the actual MW of 358.
  • Figure 2B gives similar data for DAS-2 (C 19 , H 16 , 0 9 ) showing its MW by mass spectrographic analysis in the +1 mode giving a value of 373 which is +1 above the actual MW weight of 372.
  • DAS-1 and DAS-2 protected human red blood cells from complement attack by zymogen activated serum of human, rat, cat, and dog.
  • Figure 3A illustrates the result for DAS-1.
  • IC5 0 values were 208 nM for human, 294 nM for rat, 168 nM for cat, and 142 nM for dog serum.
  • Figure 3B illustrates comparable data for DAS-2.
  • IC5 0 values of serum were 113 for human, 167 for rat, 128 for cat and 98 for dog.
  • Figure 3C shows that the precursor, acetylsalicylic acid, gave no protective effect even when added at 1 mM, which is a concentration more than 10,000 times higher than for DAS-1 and DAS-2.
  • a variation of the CH50 assay was carried out. Instead of measuring hemolysis, western blot analyses of red blood cell membranes were carried out to determine which serum complement proteins were converted into activated complement products that became attached to susceptible membranes. Such attachment only occurs up to the stage of blockade. At stages beyond the blockade, they remain unchanged in the serum. Results are shown in Figures 4 and 5. Undiluted human serum was treated for 30 min with DAS-1, DAS-2, or acetyl salicylic acid.
  • FIG. 4A Typical results for blockade of the classical pathway are shown in Figure 4A.
  • the left lane was loaded with serum only and shows that bands for Clq, C3, C4, and C5 were readily detected.
  • the adjacent lane illustrates the effect of adding to the serum zymosan to activate complement, and antibodies to properdin and Factor D to block the alternative pathway.
  • Sensitized red blood cells then become hemolyzed by classical pathway attack.
  • Native serum proteins are consumed and become incorporated into the red cell membranes.
  • Clq was not metabolized, but the band was intensified due to its dissociation from the CI complex.
  • Native C3 was no longer detected because it had been cleaved, and the C3b fragment had become covalently attached to the membrane. Its degradation product C3d was detected.
  • C4 was no longer detected because it had similarly been cleaved and the C4b fragment attached to the membrane and metabolized into its degradation product C4d. This fragment was also detected. C5 was cleaved and a band for the C5a product detected. Finally, the C5b-9 membrane attack complex, which had formed on the red cell membrane causing its hemolysis, was detected.
  • the pellets were washed two times with Hank's balanced salt solution (HBSS) and treated with sample loading buffer for SDS-PAGE and immunoblotting.
  • the buffer consisted of 50 mM Tris (pH 6.8), 0.1% SDS, 0.1% bromophenol blue and 10% glycerol. To preserve the molecular complexes that had formed, mild conditions for SDS-PAGE were followed.
  • the sample loading buffer used was 50 mM Tris (pH 6.8), 1% SDS, 0.1% bromophenol blue and 10% glycerol and 2% beta-mercaptoethanol.
  • Figure 5 shows the results when western blots were developed with monoclonal antibodies to properdin (1/2,000), C3b (1/2,000), Factor B/Bb (1/2,000) and Factor D (1/2,000) respectively.
  • Lane 1 in each blot shows that the native proteins were detected in untreated serum.
  • Lane 2 shows that in serum that has been activated by zymosan in the presence of CI inhibitor, similar bands on RBC membranes were detected by antibodies to properdin, C3b and Factor B/Bb corresponding in MW to PC3b (-240 kDa), PC3bB (-340 kDa), PC3bBb (-300 kDa) and PC3bBbC3b (>410 kDa).
  • the invention relate to methods of preventing and/or treating
  • acetyl salicylic acid dimers such as DAS-1 and DAS-2 and their isomers.
  • the compounds and compositions provided herein can be used to prevent and/or treat paroxysmal nocturnal hemoglobinemia.
  • Paroxysmal nocturnal hemoglobinemia results from a clonal deficiency in erythrocytes of the X chromosome gene PIGA.
  • the glycosal phosphatidylinositol moiety necessary for anchoring membrane proteins such as CD 55 and CD 59 is non-functional.
  • Erythrocytes and platelets lack the capacity to restrict cell-surface activation of the alternative pathway. Patients are subject to fatal thrombotic and hemolytic attacks.
  • a treatment which is partially effective is to administer at biweekly intervals the monoclonal antibody eculizumab, which blocks C5 cleavage, preventing synthesis of the membrane attack complex.
  • this treatment is less than satisfactory being effective in preventing transfusions in only 49% of patients (Hillmen et al. 2006).
  • a probable reason is that it does not block C3 convertase activity.
  • C3 convertase activity is unregulated due to the CD 55 deficiency (Parker 2002).
  • DAS-1, DAS-2 and their isomers are expected to prevent and/or treat paroxysmal nocturnal hemoglobinemia as these compounds both prevent formation of the membrane attack complex and block C3 convertase activity.
  • the compounds and compositions provided herein can be used to prevent and/or treat atypical hemolytic uremia syndrome.
  • Atypical hemolytic uremia syndrome is a chronic, life-threatening, disease caused by self-attack of the complement system. It is mainly due to mutations in Factor H, which then fails to protect cells from alternative pathway activation. Damage then occurs in endothelial cells, erythrocytes and kidney glomeruli frequently leading to kidney failure (Jokiranta et al. 2006).
  • DAS-1 and DAS-2 and their isomers are expected to prevent and/or treat atypical hemolytic uremia syndrome as these compounds inhibit the complement system, including the alternative pathway, by blocking C3 convertase activity and preventing formation of the membrane attach complex.
  • the compounds and compositions provided herein can be used to prevent and/or treat rheumatoid arthritis.
  • rheumatoid arthritis There is strong evidence that both the classical and alternative pathways of complement are pathologically activated in rheumatoid arthritis (Okroj et al. 2007).
  • the arthritic joint contains proteins capable of activating complement as well as proteins signifying that both the classical and alternative pathways have been activated.
  • resistance can be achieved by deletion of C3, C5, or Factor B (Okroj et al. 2007).
  • the compounds and compositions provided herein can be used to prevent and/or treat multiple sclerosis.
  • Multiple sclerosis is a relapsing-remitting disease characterized by inflammation of the white matter of brain.
  • Specific antibodies have been detected which target myelin antigens indicating that it is an autoimmune disorder (Compston et al., 1989). Complement will be activated in this process indicating the appropriateness of DAS- 1 and DAS-2 and their isomers in prophylaxis and/or therapy.
  • the compounds and compositions provided herein can be used to prevent and/or treat malaria infection.
  • Malaria is a prevalent disease in Africa and south East Asia, resulting in an estimated 650,000 deaths per year.
  • IgG and C3bBb complexes have been identified on erythrocytes of infected humans indicating damage caused by activation of both the classical and alternative pathways (Silver et al. 2010). Accordingly, prevention and/or treatment with DAS-1 and DAS-2 and their isomers should be effective.
  • the compounds and compositions provided herein can be used to prevent and/or treat Alzheimer's disease. It has long been known that beta amyloid protein deposits in brain, which are believed to be the primary cause of the disease, can be identified by the opsonizing components of complement. It was demonstrated that this was due to Clq binding to beta amyloid protein (Rogers et al., 1992). It was also demonstrated that the membrane attack complex of complement decorated damaged neurites in the vicinity of the deposits, indicating self-damage by the complement system (McGeer et al., 1989).
  • the compounds and compositions provided herein can be used to prevent and/or treat age-related macular degeneration.
  • Opsonizing components of complement have been identified in association with drusen, which are the extracellular deposits associated with the disease.
  • the membrane attack complex has been found near the degenerating retinal pigment epithelial cells.
  • the compounds and compositions provided herein can be used to prevent and/or treat atherosclerosis.
  • Atherosclerosis has not generally been considered to be exacerbated by the complement system.
  • C-reactive protein a known activator of complement
  • a known activator of complement is upregulated more than ten-fold in the area of atherosclerotic plaques. Plaque areas showing upregulation of C-reactive protein and the opsonization components of complement also demonstrate presence of the membrane attack complex (Yasojima et al., 2001). This is a further example of a common human degenerative condition where the membrane attack complex is present in a sterile situation and can therefore only damage host tissue. Again, the invention described here will preserve the desirable phagocytosis stimulating aspect of complement, while eliminating the self-damaging aspect of the membrane attack complex. For these reasons, DAS-1 and DAS-2 and their isomers should be an effective prophylactic and/or therapeutic treatment for atherosclerosis.
  • the invention also relate to methods of preventing and/or treating
  • inflammatory skin condition refers to a skin or scalp condition characterized by one or more of irritation, blistering, redness, flaking, localized heat, pain, itching, and hair follicle damage/destruction.
  • the compounds and compositions provided herein can be used to prevent and/or treat androgenic alopecia (baldness) is the most common form of hair loss in males. It begins after puberty, with initial losses occurring in the temporal and occipital areas. It typically advances to baldness covering the entire scalp except for a rim extending around the peripheral regions.
  • the cause is generally acknowledged to be a vulnerability of hair follicles in these areas to androgens, particularly dihydrotestosterone (DHT) (Garza et al. 2012). DHT interacts with the androgen receptor (AR) and it is high levels of this receptor that are presumed to create the vulnerability.
  • DHT dihydrotestosterone
  • AR androgen receptor
  • the compounds and compositions provided herein can be used to prevent and/or treat sunburn and thermal burns.
  • Wan et al. reported a sharp increase in C3d in burn patients as well as Factor Ba, indicating activation of the alternative complement pathway. Fluctuations over a year suggested chronic inflammation was induced (Wan et al. 1998).
  • Kang et al. in a study of patients with third-degree burns on more than 60% of the total body area, found complement consumption due to activation with survival being associated with recovery of this system (Kang et al 2003) .Such burns should respond to treatment by DAS-1 and DAS-2 and their isomers due to their effectiveness in blocking aberrant complement activation.
  • the compounds and compositions provided herein can be used to prevent and/or treat atopic or allergic dermatitis.
  • Atopic or allergic dermatitis occurs when the immune system of the skin attacks an allergen or other irritant (Seah PP et al. 1973; Triolo et al. 2003; Gober & Gaspari 2008). Keratinocytes can become damaged by this excessive attack. Through blockade of unwanted complement activation, DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the compounds and compositions provided herein can be used to prevent and/or treat pemphigus.
  • DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • Dermatitus herpetiformis is a condition which is characterized by an extremely itchy rash. It is linked to gluten intolerance and immune attack against the protein epidermal transglutaminase (Preisz et al. 2005). By inhibiting the alternative pathway at both the C3 convertase and C9 addition stages, DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the compounds and compositions provided herein can be used to prevent and/or treat psoriasis.
  • Psoriasis is a common skin condition which is characterized by an immune response (Triolo et al., 2003) which can be associated with rheumatoid arthritis (Ballanti et al., 2011).
  • DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the compounds and compositions provided herein can be used to prevent and/or treat discoid lupus erythematosis.
  • Discoid lupus erythematosis
  • erythematosis is an autoimmune disorder which is highly exacerbated by sunlight. It is currently treated with topical steroids, indicative of the effectiveness of immune blockade. It has been reported that complement is activated even in non-lesioned skin of patients with systemic erythematosus (Alahlafi et al 2005). Deposition of C5b-9 was found in the epidermis of such patients (Magro et al 1996). By blocking harmful complement activation, DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents. [0068] According to one embodiment, the compounds and compositions provided herein can be used to prevent and/or treat primary cicatricial alopecia (PC A).
  • PC A primary cicatricial alopecia
  • PC A is a skin disorder in which epithelial hair follicle stem cells are damaged or destroyed by inflammatory events (Harries et al. 2009).
  • the affected stem cells reside in the outer root sheath of hair follicle bulges (Harries et al. 2009).
  • This is an area hypothesized to be immunologically privileged (Meyer et al. 2008). Loss of such immunological privilege results in immune attack, so that hair follicles are replaced by scar tissue, with loss of hair (Harries et al. 2010).
  • a mainstay of treatment is topical steroids. Since inflammation activates the complement system, by blocking this harmful complement activation, DAS - 1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the compounds and compositions provided herein can be used to prevent and/or treat seborrheic dermatitis and dandruff.
  • Seborrheic dermatitis and dandruff are caused by an excessive loss of comeocytes from the outer layer of the epidermis (Scwartz et al., 2013). Immune dysfunction is suspected (Mills et al. 2012). The comeocytes adhere to each other creating flakes which are then shed. The pathogenesis appears to result from interactions between scalp skin, cutaneous microflora and the cutaneous immune system (Kerr et al. 2011). A proposed cause is Malassezia fungi (Gemmer et al. 2002).
  • DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the compounds and compositions provided herein can be used to prevent and/or treat alopecia areata.
  • Alopecia areata is a condition in which there is hair loss, usually from the scalp. It is characterized by a lymphocytic infiltration around vulnerable follicles, so that the hair growth disappears.
  • the standard treatment is topical corticosteroids appropriate to an inflammatory response, or minodoxil, a capillary dilator which stimulates hair growth.
  • minodoxil a capillary dilator which stimulates hair growth.
  • deposition of complement components C3, C5, and C9 are deposited in scalp hair follicles in subjects with alopecia areata (Igarashi et al 1981). By blocking this harmful complement activation which accompanies inflammation, DAS-1 and DAS-2 and their isomers should be effective prophylactic and/or therapeutic agents.
  • the one or more dimers of acetyl salicylic acid such as DAS-1 and DAS-2 and their isomers may be administered orally or parenterally.
  • one or more dimers of acetyl salicylic acid may be administered orally in the form of tablets, capsules, pills, lozenge, granule, powder, suspension, emulsion, liquid, syrup, and the like.
  • the one or more dimers may be combined with pharmaceutical acceptable carriers.
  • the one or more dimers may be combined with pharmaceutical acceptable carriers.
  • pharmaceutically acceptable carriers may prolong release, enhance effectiveness and/or decrease metabolism of the effective ingredients.
  • pharmaceutically acceptable carriers include lactose, sucrose, mannitol, hydrogenated castor oil, sorbitol, dextrin, starch, stearic acid, propylene glycol, cellulose and other ingredients that are well known to those skilled in the art.
  • one or more dimers of acetyl salicylic acid may be administered parenterally, such as intravenously, subcutaneously, and through direct injection.
  • the one or more dimers may be combined with pharmaceutical acceptable carriers such as distilled water, saline solution, balanced salt solutions, and other carriers that are well known to those skilled in the art. These modes may for example be desirable in situations where oral administration was not possible, or where high concentrations were necessary or desirable at some localized site.
  • therapeutically effective parenteral doses of the compounds of this invention for a patient will range from about 50 mg to 10 grams per day depending on the indication and needs of each particular subject.
  • the one or more dimers of acetyl salicylic acid such as DAS-1 and DAS-2 and their isomers may be administered topically.
  • the administration may be in the form of a spray, cream, ointment, gel, lotion, wash, shampoo, or lozenge, with the one more dimers being dissolved or suspended in an appropriate pharmaceutically acceptable vehicle.
  • Examples of such vehicles are glycerine as a gel, aloe vera as an ointment, sodium lauryl sulfate plus cocamidopropyl betaine as a shampoo, and eucalyptus oil and pectin for a lozenge.
  • one or more acetyl salicylic acid dimers may be administered in the form of a skin care preparation, hair care preparation or a
  • compositions formulated for application to affected areas of the skin or scalp of a patient may for example be formulated as a spray, gel, cream, lotion, stick, ointment, scrub, soap bar, tonic, roll-on formulation, sunscreen, shampoo or mousse wherein the one or more acetyl salicylic acid dimers is provided in a therapeutically effective amount together with at least one carrier so as to be capable of exerting a therapeutic effect on an inflammatory skin conditions on the patient' s skin or scalp.
  • the one or more acetyl salicylic acid dimers may be provided in such preparations or compositions at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, and may be topically applied on the affected area(s) one to five times daily for example.
  • the preparations or compositions may also include one or more of surfactants, propellants, co-solvents, gelling agent, and other ingredients suitable for use in skin or hair care preparations of the type known in the art, such as petrolatum, waxes, oils plasticizers, preservatives, fragrances and the like.
  • the preparations or compositions may be applied to the skin or scalp of a patient using bottles or containers (e.g. shampoos), tubes (e.g. gels, creams, ointments, lotions), pressurized canisters (e.g. sprays, mousses), pads, sticks, or "roll-on” applicators (e.g. gels, ointments).
  • bottles or containers e.g. shampoos
  • tubes e.g. gels, creams, ointments, lotions
  • pressurized canisters e.g. sprays, mousses
  • pads e.g. gels, ointments
  • rolls-on applicators e.g. gels, ointments
  • the preparations or compositions may be formulated to form a film over the skin or scalp, thus allowing controlled release and penetration of the one or more acetyl salicylic acid dimers such as DAS-1 and DAS-2 and their isomers into the affected areas.
  • the one or more acetyl salicylic acid dimers may be provided at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, in an aqueous shampoo base comprising the surfactants sodium lauryl sulfate and cocamidopropyl betaine, for application to the scalp.
  • the one or more acetyl salicylic acid dimers may be provided at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, in an ointment comprising glycerin, for application to the skin or scalp.
  • the one or more acetyl salicylic acid dimers may be provided at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, in a gel comprising aloe vera, for application to the skin or scalp.
  • the one or more acetyl salicylic acid dimers may be dissolved at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, in water and applied as a spray or other means to the affected skin or scalp area.
  • the one or more acetyl salicylic acid dimers may be provided at a concentration of 0.1 to 100 mg/mL, or 0.1 to 10 mg/mL, or 0.5 to 5 mg/mL, in a sunscreen formulation comprising one or more known active sunscreen ingredients.

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Abstract

L'invention concerne des dimères de l'acide acétylsalicylique, y compris l'acide 4,4'-diacétoxy-[1,1'-biphényle]-3,3'-dicarboxylique (DAS-1) et l'acide 5,5'-méthylènebis(2-acétoxybenzoïque) (DAS-2). Des procédés sont aussi fournis pour bloquer le stade C3 convertase de la voie alternative du complément, prévenir la formation du complexe d'attaque membranaire du complément, et prévenir ou traiter un trouble médié par le complément chez un mammifère, y compris l'étape d'administration de dimères de l'acide acétylsalicylique.
PCT/CA2014/051097 2013-11-18 2014-11-17 Dimères de l'acide acétylsalicylique, leur synthèse, et leurs utilisations pour prévenir et traiter des troubles médiés par le complément WO2015070354A1 (fr)

Priority Applications (5)

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EP14862004.0A EP3071543B1 (fr) 2013-11-18 2014-11-17 Dimères de l'acide acétylsalicylique, leur synthèse, et leurs utilisations pour prévenir et traiter des troubles médiés par le complément
ES14862004T ES2774776T3 (es) 2013-11-18 2014-11-17 Dímeros de ácido acetilsalicílico, síntesis de los mismos, y usos de los mismos para prevenir y tratar trastornos mediados por complemento
CA2930459A CA2930459A1 (fr) 2013-11-18 2014-11-17 Dimeres de l'acide acetylsalicylique, leur synthese, et leurs utilisations pour prevenir et traiter des troubles medies par le complement
JP2016553687A JP6464180B2 (ja) 2013-11-18 2014-11-17 アセチルサリチル酸ダイマー、その合成、ならびに補体媒介性障害の予防および治療のためのその使用
US15/036,212 US9751824B2 (en) 2013-11-18 2014-11-17 Acetyl salicyclic acid dimers, synthesis thereof, and uses thereof to prevent and treat complement-mediated disorders

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US201361905596P 2013-11-18 2013-11-18
US61/905,596 2013-11-18

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EP3201166A4 (fr) * 2014-07-18 2018-06-27 Biocogent, LLC Compositions et procédés comprenant des salicylates et des polysalicylates
US11013750B2 (en) 2017-01-20 2021-05-25 Aurin Biotech Inc. Methods for treating and preventing nociceptive pain

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CA3059278A1 (fr) * 2017-05-31 2018-12-06 Aurin Biotech Inc. Methodes de diagnostic et de traitement de la cachexie

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EP3201166A4 (fr) * 2014-07-18 2018-06-27 Biocogent, LLC Compositions et procédés comprenant des salicylates et des polysalicylates
US11013750B2 (en) 2017-01-20 2021-05-25 Aurin Biotech Inc. Methods for treating and preventing nociceptive pain

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US9751824B2 (en) 2017-09-05
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JP6464180B2 (ja) 2019-02-06
EP3071543A1 (fr) 2016-09-28
EP3071543A4 (fr) 2017-07-26
ES2774776T3 (es) 2020-07-22
US20160297743A1 (en) 2016-10-13
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